Based on preclinical data on nicotine-opioid system interactions and preliminary data from the original project, the current application proposes to evaluate whether genetic variation in the mu opioid receptor (OPRM1 ) predicts response to standard versus extended transdermal nicotine (TN) therapy. The OPRM1 Asp40 variant increases the binding affinity of beta-endorphin for this receptor by three-fold, relative to the wild-type Asn40 OPRM1. Since nicotine increases release of beta-endorphin, we hypothesized in the original project that smokers with the OPRMI Asp40 variant would have better outcomes with NRT. The results showed that smokers carrying the OPRMl Asp40 variant were significantly more likely than those homozygous for the Asn40 variant to be abstinent at the end of TN treatment. Moreover, the differential treatment response was most pronounced during the 21 mg dose phase of TN, reduced as TN was tapered, and was no longer present after treatment was discontinued. We propose to replicate and extend these findings by conducting randomized placebo-controlled trial to determine the effects of standard treatment (ST) versus extended treatment (ET) with TN among smokers genotyped for the OPRMI Asn40Asp variant. Equal numbers of smokers with the Asn40 (n=300) and Asp40 (n=300) variants will be randomized to receive either standard treatment with TN (21 mg x 4 weeks, 14mg x 2 weeks, 7 mg x 2 weeks, placebo x 16 weeks) or extended treatment with TN (21 mg x 20 weeks, 14mg x 2 weeks, 7 mg x 2 weeks). The primary outcome will be biochemically verified 7-day point prevalence abstinence from smoking at 20 weeks (end of 21mg dose phase of treatment). Secondary outcomes include logitudinal smoking phenotypes and abstinence symptoms. The ultimate objective of this research is to identify smokers who benefit from extended TN treatment based on genetic information.